The human immunodeficiency virus (HIV-1) is the cause of AIDS. The primary target for antibodies capable of neutralizing the HIV-1 infection process is the exterior envelope glycoprotein, gp120. Although gp120 exists on the surface of the virus in non-covalent association with the trimeric transmembrane glycoprotein, gp41, shed monomeric gp120 is thought to be the major immunogen in vivo. The development of a broadly effective HIV-1 vaccine is obviously of extremely high priority. Such a vaccine will likely need to efficiently elicit broadly neutralizing antibodies directed against HIV envelope glycoproteins, as well as avid cellular responses directed against virus-specific CTL epitopes. The generation of a mature antibody response requires the assistance of adequate T cell help from activated CD4+ helper T cells. The ability of HIV-1 to destroy activated CD4+ T lymphocytes, many of which exhibit helper phenotypes, has led to the suggestion that defects in T cell help may facilitate viral persistence. We have preliminary evidence that strongly suggests that modified gp120 immunogens are deficient in T cell helper epitopes. These glycoproteins are extremely poor in eliciting antibody responses. The addition of pan-reactive (PADRE), heterologous T cell helper epitopes restores the ability of these glycoproteins to elicit high-titer, gp120-specific antibodies. In this proposal, we plan to further investigate this phenomenon and assess the ability of heterologous T helper epitopes to augment gp120-specific antibody responses. A second aim of the proposal is to conformationally stabilize one of the modified immunogens, based upon some very recent thermodynamic analysis of gp120, in a manner that may more efficiently elicit broadly neutralizing antibodies. This work may have important implications for HIV-1 vaccine design.